2',4'-Dihydroxyacetophenone (I) was selectively alkylated at position 4' with 1-bromo-3-chloropropane (II) in the presence of K2CO3 in refluxing acetone to yield the 4'-(3-chloropropyl)ether (III). Further condensation of (III) with Vilsmeier reagent, followed by aqueous work up, provided the 3-formylchromenone (IV), which was subsequently reduced with sodium borohydride in CHCl3-EtOH at 0 C to give the (hydroxymethyl)chromenone (V). Finally, alkylation of 6-fluoro-3-(4-piperidinyl)-1,2-benzisoxazole (VI) with chloride (V) in the presence of K2CO3 and KI in refluxing acetonitrile yielded the title compound, which was isolated as the hydrochloride salt from methanol.
Methyl 2,4-dihydroxybenzoate (VII) was selectively protected as the 4-benzyl ether (VIII) with benzyl bromide in the presence of potassium carbonate. Condensation with sodium (methylsulfinyl)methyde provided the corresponding methylsulfinyl ketone (IX). This was condensed with two equivalents of formaldehyde to yield (X). Subsequent pyrolysis of the sulfoxide group furnished chromenone (XI). Deprotection of the benzyl ether was achieved by treatment with boron trichloride, and the resulting 7-hydroxychromenone (XII) was then alkylated with 1-bromo-3-chloropropane (II) to give 7-(3-chloropropoxy)-3-(hydroxymethyl)-4H-chromen-4-one (V).
Since this synthetic method did not allow the scale-up preparation, mainly due to safety concerns regarding the use of sodium (methylsulfinyl)methyde, an improved and scalable procedure was further developed. Claisen condensation of acetophenone (III) with ethyl formate in the presence of sodium methoxide produced the 2-hydroxychromanone (XIII). This was condensed with formaldehyde, employing sodium acetate as the catalyst, and the intermediate 3-(hydroxymethyl)-2-hydroxychromanone (XIV) was subsequently dehydrated by treatment with HCl to give (V).